Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Thomas R. Webb; Jeanette Erdmann; Kathleen E. Stirrups; Nathan O. Stitziel; Nicholas G.D. Masca; Henning Jansen; Stavroula Kanoni; Christopher P. Nelson; Paola G. Ferrario; Inke R. König; John D. Eicher; Andrew D. Johnson; Stephen E. Hamby; Christer Betsholtz; Arno Ruusalepp; Oscar Franzén; Eric E. Schadt; Johan L.M. Björkegren; Peter E. Weeke; Paul L. Auer; Ursula M. Schick; Yingchang Lu; He Zhang; Marie-Pierre Dube; Anuj Goel; Martin Farrall; Gina M. Peloso; Hong-Hee Won; Ron Do; Erik van Iperen; Jochen Kruppa; Anubha Mahajan; Robert A. Scott; Christina Willenborg; Peter S. Braund; Julian C. van Capelleveen; Alex S.F. Doney; Louise A. Donnelly; Rosanna Asselta; Pier A. Merlini; Stefano Duga; Nicola Marziliano; Josh C. Denny; Christian Shaffer; Nour Eddine El-Mokhtari; Andre Franke; Stefanie Heilmann; Christian Hengstenberg; Per Hoffmann; Oddgeir L. Holmen; Kristian Hveem; Jan-Håkan Jansson; Karl-Heinz Jöckel; Thorsten Kessler; Jennifer Kriebel; Karl L. Laugwitz; Eirini Marouli; Nicola Martinelli; Mark I. McCarthy; Natalie R. Van Zuydam; Christa Meisinger; Tõnu Esko; Evelin Mihailov; Stefan A. Escher; Maris Alver; Susanne Moebus; Andrew D. Morris; Jarma Virtamo; Majid Nikpay; Oliviero Olivieri; Sylvie Provost; Alaa AlQarawi; Neil R. Robertson; Karen O. Akinsansya; Dermot F. Reilly; Thomas F. Vogt; Wu Yin; Folkert W. Asselbergs; Charles Kooperberg; Rebecca D. Jackson; Eli Stahl; Martina Müller-Nurasyid; Konstantin Strauch; Tibor V. Varga; Melanie Waldenberger; Lingyao Zeng; Rajiv Chowdhury; Veikko Salomaa; Ian Ford; J. Wouter Jukema; Philippe Amouyel; Jukka Kontto; Børge G. Nordestgaard; Jean Ferrières; Danish Saleheen; Naveed Sattar; Praveen Surendran; Aline Wagner; Robin Young; Joanna M.M. Howson; Adam S. Butterworth; John Danesh; Diego Ardissino; Erwin P. Bottinger; Raimund Erbel; Paul W. Franks; Domenico Girelli; Alistair S. Hall; G. Kees Hovingh; Adnan Kastrati; Wolfgang Lieb; Thomas Meitinger; William E. Kraus; Svati H. Shah; Ruth McPherson; Marju Orho-Melander; Olle Melander; Andres Metspalu; Colin N.A. Palmer; Annette Peters; Daniel J. Rader; Muredach P. Reilly; Ruth J.F. Loos; Alex P. Reiner; Dan M. Roden; Jean-Claude Tardif; John R. Thompson; Nicholas J. Wareham; Hugh Watkins; Cristen J. Willer; Nilesh J. Samani; Heribert Schunkert; Panos Deloukas; Sekar Kathiresan; Wellcome Trust Case Control Consortium

doi:10.1016/j.jacc.2016.11.056

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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

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Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease

Thomas R. Webb, Jeanette Erdmann, Kathleen E. Stirrups, Nathan O. Stitziel, Nicholas G.D. Masca, Henning Jansen, Stavroula Kanoni, Christopher P. Nelson, Paola G. Ferrario, Inke R. König, …

Journal of the American College of Cardiology, Vol.69(7), pp.823-836

21/02/2017

DOI: https://doi.org/10.1016/j.jacc.2016.11.056

PMCID: PMC5314135

PMID: 28209224

Abstract

cholesteryl ester transfer protein

expression quantitative trait loci

genetics

genome-wide association

single nucleotide polymorphism

Genome-wide association studies have so far identified 56 loci associated with risk of coronary artery disease (CAD). Many CAD loci show pleiotropy; that is, they are also associated with other diseases or traits. This study sought to systematically test if genetic variants identified for non-CAD diseases/traits also associate with CAD and to undertake a comprehensive analysis of the extent of pleiotropy of all CAD loci. In discovery analyses involving 42,335 CAD cases and 78,240 control subjects we tested the association of 29,383 common (minor allele frequency >5%) single nucleotide polymorphisms available on the exome array, which included a substantial proportion of known or suspected single nucleotide polymorphisms associated with common diseases or traits as of 2011. Suggestive association signals were replicated in an additional 30,533 cases and 42,530 control subjects. To evaluate pleiotropy, we tested CAD loci for association with cardiovascular risk factors (lipid traits, blood pressure phenotypes, body mass index, diabetes, and smoking behavior), as well as with other diseases/traits through interrogation of currently available genome-wide association study catalogs. We identified 6 new loci associated with CAD at genome-wide significance: on 2q37 (KCNJ13-GIGYF2), 6p21 (C2), 11p15 (MRVI1-CTR9), 12q13 (LRP1), 12q24 (SCARB1), and 16q13 (CETP). Risk allele frequencies ranged from 0.15 to 0.86, and odds ratio per copy of the risk allele ranged from 1.04 to 1.09. Of 62 new and known CAD loci, 24 (38.7%) showed statistical association with a traditional cardiovascular risk factor, with some showing multiple associations, and 29 (47%) showed associations at p < 1 × 10−4 with a range of other diseases/traits. We identified 6 loci associated with CAD at genome-wide significance. Several CAD loci show substantial pleiotropy, which may help us understand the mechanisms by which these loci affect CAD risk. [Display omitted]

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Title: Systematic Evaluation of Pleiotropy Identifies 6 Further Loci Associated With Coronary Artery Disease
Creators - without role: Thomas R. Webb - University of Leicester
Jeanette Erdmann - University of Lübeck
Kathleen E. Stirrups - University of Cambridge
Nathan O. Stitziel - Washington University in St. Louis
Nicholas G.D. Masca - University of Leicester
Henning Jansen - Deutsches Herzzentrum München
Stavroula Kanoni - Queen Mary University of London
Christopher P. Nelson - University of Leicester
Paola G. Ferrario - University of Lübeck
Inke R. König - University of Lübeck
John D. Eicher - Framingham Heart Study
Andrew D. Johnson - National Heart Lung and Blood Institute
Stephen E. Hamby - University of Leicester
Christer Betsholtz - Uppsala University
Arno Ruusalepp - University of Tartu
Oscar Franzén - Clinical Gene Networks
Eric E. Schadt - Icahn School of Medicine at Mount Sinai
Johan L.M. Björkegren - Karolinska Institutet
Peter E. Weeke - Vanderbilt University Medical Center
Paul L. Auer - University of Wisconsin–Milwaukee
Ursula M. Schick - Hutchinson
Yingchang Lu - Icahn School of Medicine at Mount Sinai
He Zhang - University of Leicester
Marie-Pierre Dube - Université de Montréal
Anuj Goel - University of Oxford
Martin Farrall - University of Oxford
Gina M. Peloso - Massachusetts General Hospital
Hong-Hee Won - Massachusetts General Hospital
Ron Do - Icahn School of Medicine at Mount Sinai
Erik van Iperen - Academic Medical Center
Jochen Kruppa - University of Veterinary Medicine
Anubha Mahajan - University of Oxford
Robert A. Scott - MRC Epidemiology Unit
Christina Willenborg - University of Lübeck
Peter S. Braund - University of Leicester
Julian C. van Capelleveen - Academic Medical Center
Alex S.F. Doney - University of Dundee
Louise A. Donnelly - University of Dundee
Rosanna Asselta - University of Milan
Pier A. Merlini - Mylan
Stefano Duga - University of Milan
Nicola Marziliano - ASL Roma
Josh C. Denny - Vanderbilt University Medical Center
Christian Shaffer - Vanderbilt University Medical Center
Nour Eddine El-Mokhtari - Klinik für Kardiologie, Pneumologie und Innere Medizin, Imland Klinik Rendsburg, Rendsburg, Germany
Andre Franke - Framingham Heart Study
Stefanie Heilmann - University of Bonn
Christian Hengstenberg - McDonnell Genome Institute, Washington University School of Medicine, Saint Louis, Missouri
Per Hoffmann - University of Bonn
Oddgeir L. Holmen - Norwegian University of Science and Technology
Kristian Hveem - Norwegian University of Science and Technology
Jan-Håkan Jansson - Umeå University
Karl-Heinz Jöckel - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany
Thorsten Kessler - Deutsches Herzzentrum München, Technische Universität München, München, Germany
Jennifer Kriebel - Helmholtz Zentrum München
Karl L. Laugwitz - DZHK, Partner Site Munich Heart Alliance, Munich, Germany
Eirini Marouli - Queen Mary University of London
Nicola Martinelli - University of Verona
Mark I. McCarthy - University of Oxford
Natalie R. Van Zuydam - University of Oxford
Christa Meisinger - Helmholtz Zentrum München
Tõnu Esko - University of Tartu
Evelin Mihailov - University of Tartu
Stefan A. Escher - Lund University
Maris Alver - University of Tartu
Susanne Moebus - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany
Andrew D. Morris - Framingham Heart Study
Jarma Virtamo - National Institute for Health and Welfare (THL), Helsinki, Finland
Majid Nikpay - University of Ottawa
Oliviero Olivieri - University of Verona
Sylvie Provost - Montreal Heart Institute
Alaa AlQarawi - King Abdulaziz University
Neil R. Robertson - University of Oxford
Karen O. Akinsansya - Merck Sharp & Dohme, Rahway, New Jersey
Dermot F. Reilly - MSD
Thomas F. Vogt - Merck Sharp & Dohme, Rahway, New Jersey
Wu Yin - Merck Sharp & Dohme, Rahway, New Jersey
Folkert W. Asselbergs - University Medical Center Utrecht
Charles Kooperberg - Hutchinson
Rebecca D. Jackson - The Ohio State University
Eli Stahl - Icahn School of Medicine at Mount Sinai
Martina Müller-Nurasyid - DZHK, Partner Site Munich Heart Alliance, Munich, Germany
Konstantin Strauch - Helmholtz Zentrum München
Tibor V. Varga - Lund University
Melanie Waldenberger - Helmholtz Zentrum München
Lingyao Zeng - Deutsches Herzzentrum München, Technische Universität München, München, Germany
Rajiv Chowdhury - University of Cambridge
Veikko Salomaa - National Institute for Health and Welfare (THL), Helsinki, Finland
Ian Ford - University of Glasgow
J. Wouter Jukema - Leiden University Medical Center
Philippe Amouyel - Facteurs de risque et déterminants moléculaires des maladies liées au vieillissement
Jukka Kontto - National Institute for Health and Welfare (THL), Helsinki, Finland
Børge G. Nordestgaard - Copenhagen University Hospital
Jean Ferrières - University of Lübeck
Danish Saleheen - University of Pennsylvania
Naveed Sattar - University of Glasgow
Praveen Surendran - Institute of Medical Informatics, Biometry and Epidemiology, Chair of Genetic Epidemiology, Ludwig-Maximilians-Universität, Munich, Germany
Aline Wagner - University of Strasbourg
Robin Young - University of Cambridge
Joanna M.M. Howson - University of Cambridge
Adam S. Butterworth - University of Cambridge
John Danesh - University of Cambridge
Diego Ardissino - Parma University Hospital, Parma, Italy
Erwin P. Bottinger - Icahn School of Medicine at Mount Sinai
Raimund Erbel - Institute for Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany
Paul W. Franks - Lund University
Domenico Girelli - University of Verona
Alistair S. Hall - University of Leeds
G. Kees Hovingh - Academic Medical Center
Adnan Kastrati - Deutsches Herzzentrum München, Technische Universität München, München, Germany
Wolfgang Lieb - Institute of Epidemiology and Biobank popgen, Christian-Albrechts-University Kiel, Kiel, Germany
Thomas Meitinger - DZHK, Partner Site Munich Heart Alliance, Munich, Germany
William E. Kraus - Duke University
Svati H. Shah - Duke University
Ruth McPherson - University of Ottawa
Marju Orho-Melander - Lund University
Olle Melander - Lund University
Andres Metspalu - University of Tartu
Colin N.A. Palmer - University of Dundee
Annette Peters - DZHK, Partner Site Munich Heart Alliance, Munich, Germany
Daniel J. Rader - University of Pennsylvania
Muredach P. Reilly - Columbia University
Ruth J.F. Loos - Icahn School of Medicine at Mount Sinai
Alex P. Reiner - Fred Hutchinson Cancer Research Center, Seattle, Washington
Dan M. Roden - Vanderbilt University Medical Center
Jean-Claude Tardif - Université de Montréal
John R. Thompson - NIHR Leicester Cardiovascular Biomedical Research Unit
Nicholas J. Wareham - MRC Epidemiology Unit
Hugh Watkins - University of Oxford
Cristen J. Willer - Université de Montréal
Nilesh J. Samani - University of Leicester
Heribert Schunkert - Deutsches Herzzentrum München, Technische Universität München, München, Germany
Panos Deloukas - Queen Mary University of London
Sekar Kathiresan - Massachusetts General Hospital
Wellcome Trust Case Control Consortium
Publication Details: Journal of the American College of Cardiology, Vol.69(7), pp.823-836
Publisher: Elsevier Inc
Identifiers: 9940587708331
Academic Unit: King Abdulaziz University
Language: English
Resource Type: Journal article